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Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants
Ubiquilin-2 (UBQLN2) is a ubiquitin-binding protein that shuttles ubiquitinated proteins to proteasomal and autophagic degradation. UBQLN2 mutations are genetically linked to the neurodegenerative disorders amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). However, it remains elus...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Life Science Alliance LLC
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9258132/ https://www.ncbi.nlm.nih.gov/pubmed/35777956 http://dx.doi.org/10.26508/lsa.202101327 |
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author | Strohm, Laura Hu, Zehan Suk, Yongwon Rühmkorf, Alina Sternburg, Erin Gattringer, Vanessa Riemenschneider, Henrick Berutti, Riccardo Graf, Elisabeth Weishaupt, Jochen H Brill, Monika S Harbauer, Angelika B Dormann, Dorothee Dengjel, Jörn Edbauer, Dieter Behrends, Christian |
author_facet | Strohm, Laura Hu, Zehan Suk, Yongwon Rühmkorf, Alina Sternburg, Erin Gattringer, Vanessa Riemenschneider, Henrick Berutti, Riccardo Graf, Elisabeth Weishaupt, Jochen H Brill, Monika S Harbauer, Angelika B Dormann, Dorothee Dengjel, Jörn Edbauer, Dieter Behrends, Christian |
author_sort | Strohm, Laura |
collection | PubMed |
description | Ubiquilin-2 (UBQLN2) is a ubiquitin-binding protein that shuttles ubiquitinated proteins to proteasomal and autophagic degradation. UBQLN2 mutations are genetically linked to the neurodegenerative disorders amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). However, it remains elusive how UBQLN2 mutations cause ALS/FTD. Here, we systematically examined proteomic and transcriptomic changes in patient-derived lymphoblasts and CRISPR/Cas9–engineered HeLa cells carrying ALS/FTD UBQLN2 mutations. This analysis revealed a strong up-regulation of the microtubule-associated protein 1B (MAP1B) which was also observed in UBQLN2 knockout cells and primary rodent neurons depleted of UBQLN2, suggesting that a UBQLN2 loss-of-function mechanism is responsible for the elevated MAP1B levels. Consistent with MAP1B’s role in microtubule binding, we detected an increase in total and acetylated tubulin. Furthermore, we uncovered that UBQLN2 mutations result in decreased phosphorylation of MAP1B and of the ALS/FTD–linked fused in sarcoma (FUS) protein at S439 which is critical for regulating FUS-RNA binding and MAP1B protein abundance. Together, our findings point to a deregulated UBQLN2-FUS-MAP1B axis that may link protein homeostasis, RNA metabolism, and cytoskeleton dynamics, three molecular pathomechanisms of ALS/FTD. |
format | Online Article Text |
id | pubmed-9258132 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Life Science Alliance LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-92581322022-07-19 Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants Strohm, Laura Hu, Zehan Suk, Yongwon Rühmkorf, Alina Sternburg, Erin Gattringer, Vanessa Riemenschneider, Henrick Berutti, Riccardo Graf, Elisabeth Weishaupt, Jochen H Brill, Monika S Harbauer, Angelika B Dormann, Dorothee Dengjel, Jörn Edbauer, Dieter Behrends, Christian Life Sci Alliance Research Articles Ubiquilin-2 (UBQLN2) is a ubiquitin-binding protein that shuttles ubiquitinated proteins to proteasomal and autophagic degradation. UBQLN2 mutations are genetically linked to the neurodegenerative disorders amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). However, it remains elusive how UBQLN2 mutations cause ALS/FTD. Here, we systematically examined proteomic and transcriptomic changes in patient-derived lymphoblasts and CRISPR/Cas9–engineered HeLa cells carrying ALS/FTD UBQLN2 mutations. This analysis revealed a strong up-regulation of the microtubule-associated protein 1B (MAP1B) which was also observed in UBQLN2 knockout cells and primary rodent neurons depleted of UBQLN2, suggesting that a UBQLN2 loss-of-function mechanism is responsible for the elevated MAP1B levels. Consistent with MAP1B’s role in microtubule binding, we detected an increase in total and acetylated tubulin. Furthermore, we uncovered that UBQLN2 mutations result in decreased phosphorylation of MAP1B and of the ALS/FTD–linked fused in sarcoma (FUS) protein at S439 which is critical for regulating FUS-RNA binding and MAP1B protein abundance. Together, our findings point to a deregulated UBQLN2-FUS-MAP1B axis that may link protein homeostasis, RNA metabolism, and cytoskeleton dynamics, three molecular pathomechanisms of ALS/FTD. Life Science Alliance LLC 2022-07-01 /pmc/articles/PMC9258132/ /pubmed/35777956 http://dx.doi.org/10.26508/lsa.202101327 Text en © 2022 Strohm et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Articles Strohm, Laura Hu, Zehan Suk, Yongwon Rühmkorf, Alina Sternburg, Erin Gattringer, Vanessa Riemenschneider, Henrick Berutti, Riccardo Graf, Elisabeth Weishaupt, Jochen H Brill, Monika S Harbauer, Angelika B Dormann, Dorothee Dengjel, Jörn Edbauer, Dieter Behrends, Christian Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants |
title | Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants |
title_full | Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants |
title_fullStr | Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants |
title_full_unstemmed | Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants |
title_short | Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants |
title_sort | multi-omics profiling identifies a deregulated fus-map1b axis in als/ftd–associated ubqln2 mutants |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9258132/ https://www.ncbi.nlm.nih.gov/pubmed/35777956 http://dx.doi.org/10.26508/lsa.202101327 |
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